ANTICANCER RESEARCH 38 : 5429-5436 (2018) doi:10.21873/anticanres.12874

Outcome of Patients with Metastatic Castration-resistant Prostate Cancer After PSA Progression with Abiraterone Acetate SHENG-CHUN HUNG 1,2 , SHIAN-SHIANG WANG 1,2,3 , JIAN-RI LI 1,4 , MEI-CHIH CHEN 1, CHENG-KUANG YANG 1, CHUAN-SHU CHEN 1,2 , HAO-CHUNG HO 1, KUN-YUAN CHIU 1,3 , CHEN-LI CHENG 1,2 , CHAO-HSIANG CHANG 5 and YEN-CHUAN OU 1,2,6

1Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.; 2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C.; 3Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan, R.O.C.; 4Department of Medicine and Nursing, Hungkuang University, Taichung, Taiwan, R.O.C.; 5Department of Urology, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 6Department of Medical Research, Tungs’ Taichung Metroharbor Hospital, Taichung, Taiwan, R.O.C.

Abstract. Background/Aim: The main purpose of this study months, p=0.126). Patients with AA treatment who received was to evaluate the outcome of patients with prostate-specific subsequent therapies after PSA progression had better overall antigen (PSA) progression after abiraterone acetate (AA) survival than those without (18 vs. 4 months, p=0.003). In treatment for metastatic castration-resistant prostate cancer addition, there was a trend for better chemotherapy response (mCRPC). Patients and Methods: Between 2012 and 2017, in AA non-responders than AA responders, 62.5% (5/8) vs. 83 patients with clinically-confirmed mCRPC previously 12.5% (1/8) respectively. Conclusion: In our small treated with docetaxel with/without cabazitaxel followed by retrospective patient experience, effective sequential AA were included in this retrospective study. All patients treatments for patients with mCRPC provided overall survival received 1,000 mg AA with 5 or 10 mg prednisolone. Among benefit. Previous treatment response can act as a clinical them, 59 were eligible for this study based on PSA predictor for subsequent treatment. progression during the clinical course. Patients were divided into two groups, AA responders and AA non-responders Prostate cancer formation and progression relate to the according to previous PSA response to AA treatment. Overall activation of androgen receptor (AR). Intercepting androgen- survival and treatment response to subsequent therapy were related signaling has been the therapeutic strategy and AR- analyzed. Results: The median overall survival of the 59 targeted agents have been the mainstay treatment for patients after AA-treated PSA progression was 12 (95% metastatic prostate cancer for decades (1). Androgen confidence interval(CI)=7.6-16.4) months and was longer in blockade, as well as surgical or medical castration, are not the AA-responding group compared to the non-responding curative and disease may, therefore, progress into advanced group (25 vs. 8 months, p<0.001). The survival time after or metastatic disease at a later stage. Disease may also PSA progression on AA was longer in the AA-responsive progress to an AR-resistant stage at which hormonal therapy group despite not being statistically different (13 vs. 7 is no longer effective, so called castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC). To compensate for hormonal therapy, Correspondence to: Yen-Chuan Ou, Division of Urology, docetaxel, first introduced in 2003, is applied as non- Department of Surgery, Taichung Veterans General Hospital, hormonal systemic treatment to prolong the survival of Taichung, No. 1650, Sec. 4, Taiwan Boulevard, Taichung, Postal patients with mCRPC (2). Abiraterone acetate (AA) is a code 40705, Taiwan, R.O.C. Tel: +886 23741215, Fax: +8864 potent and selective inhibitor of cytochrome P450 , family 23593160, e-mail: [email protected]; Sheng-Chun Hung, 17, subfamily A, polypeptide 1 (CYP17A1), which is a Division of Urology, Department of Surgery, Taichung Veterans critical enzyme in androgen biosynthesis. Administration of General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Taichung, AA may block androgen production in adrenal glands, testes Postal code 40705, Taiwan, R.O.C. Tel: +886 919031517, Fax: +886 423593160, e-mail: [email protected] and even the prostate tumor, thus leading to the decline of testosterone both in circulation and in intra-prostatic tissues. Key Words: Abiraterone acetate, metastatic castration-resistant That a therapeutic effect of AA in mCRPC has been achieved prostate cancer, progression, PSA, survival. is based on PSA response, symptom improvement and tumor

5429 ANTICANCER RESEARCH 38 : 5429-5436 (2018) shrinkage (3-5). Additionally, randomized placebo-controlled Solid Tumors (RECIST), soft-tissue PD was defined as the target phase III clinical trial of AA with prednisolone demonstrated lesion in soft-tissue sites ( i.e. , liver or lung) or lymph nodes the overall survival benefit in patients with mCRPC enlarged ≥2 cm in diameter (12). If there were two or more new lesions on a bone scan, this was defined as bone PD (11). When previously treated with docetaxel, with 15.8 months bone scan results suggested a flare reaction or trauma, other imaging compared to 11.2 month in the placebo-treated arm (6, 7). modalities, such as computed tomography, was used for Treatment efficacy was also examined in Asian patient confirmation. Patients who developed PSA progression after AA groups in a phase II study, demonstrating a median overall treatment were to receive re-challenge of chemotherapy with survival of 11.8 months and a response rate of 43%, thus docetaxel, cabazitaxel, or another second-line therapy of implying that the combination of AA and prednisolone is a enzalutamide depending on clinical symptoms, such as a good favorable second-line treatment (8). performance status and affordability. Docetaxel was administered intravenously at 75 mg/m 2 once every 3 weeks or 50 mg/m 2 once At our institution, AA has been administered post- every 2 weeks up to 14 cycles if tolerated. chemotherapy to patients with mCRPC since 2012. We The study end-point was overall survival, defined as the time reported that the duration of first-line androgen deprivation from AA treatment to any cause of death. therapy (ADT) is positively associated with AA treatment The Mann–Whitney U-test and Fisher’s exact t- test were used for efficacy in terms of progression-free and overall survival (9). continuous variables, while the chi-squared test was used for Despite the survival benefit of AA treatment observed, the categorical variables. Kaplan–Meier survival curve with log-rank progression of disease in subsequent months is inevitable. test was used for evaluating the overall survival between the two groups. All statistical tests were carried out using IBM SPSS version Continued application of AA, re-challenge with docetaxel, 22 for Windows (IBM Corp., Armonk, NY, USA), with a p-value of or a switch to enzalutamide or radioisotope therapy may be less than 0.05 considered statistically significant. options for patients with mCRPC unresponsive to second- line AA therapy (10). There is neither a standard treatment Results nor appropriate diagnostic markers to accurately determine subsequent therapy for such cases. To clarify what happens The basic characteristics of all the 59 patients with mCRPC to patients with mCRPC which had progressed after AA before AA treatment are shown in Table I. The median age treatment and further investigate favorable therapeutic of diagnosis was 65 years, and the median first line duration strategies after AA is invalidated, we conducted a clinical of ADT was 20 months. Docetaxel was given with a median investigation of the responses and outcomes of patients with of six cycles as first-line therapy after the development of mCRPC who had PSA progression after AA treatment. mCRPC. Nineteen of these patients (19/59, 32.2%) received cabazitaxel after failed docetaxel treatment. Patients and Methods Table II demonstrates the characteristics of patients who developed PSA progression after AA treatment. For the whole From April 2012 to March 2017, a total of 83 patients with mCRPC patient group, the median follow-up time was 11 months who had been treated with docetaxel followed by AA treatment (interquartile range (IQR)=7-20 months), and 38 patients had were retrospectively reviewed from our institute. Written informed died by the cutoff time. The median AA treatment duration was consent was obtained from all the included patients before 7 months in the responsive group compared to 2 months in the treatment, according to the certification of the Institute Review p< Board of Taichung Veterans General Hospital, number CE13240A- non-responsive group ( 0.001). Except for PSA progression, 2. All these patients received 1000 mg AA plus 5 or 10 mg a total of 42 patients (42/59, 71.3%) also had radiologically prednisolone once daily combined with continued ADT. proven disease progression. Among them, 22 patients had soft- Fifty-nine patients who had PSA progression after AA were tissue PD, 38 had bone PD, and 18 patients were diagnosed retrospectively reviewed for this study and were grouped into AA- with both types of progression. After PSA progression responsive (n=26) and -non-responsive groups (n=33). PSA response developed, eight patients of each group received re-challenge was characterized as a decrease in PSA of at least 50% from chemotherapy with docetaxel or cabazitaxel. There was a better baseline. All the patients were under a castration level of <50 ng/dl testosterone during the clinical course; the clinical discrimination of response rate to chemotherapy re-challenge in the AA-non- patients is described in Figure 1. responsive group (responsive vs. non-responsive groups, 12.5% The development of CRPC was characterized based on a vs. 62.5%, p= 0.039). A total of 13 patients received continuous rise of serum PSA, the progression of pre-existing enzalutamide after AA failed, and five of them (38.5%) disease, or the appearance of new metastasis under castration levels achieved a decrease in PSA of 50%, with a higher response rate of testosterone (<50 ng/dl). According to the criteria of the Prostate in the AA-responsive group (40.0% vs. 33.3%, p= 0.835). Cancer Working Group’s second publication (PCWG2), progressive The median duration of survival after AA treatment failed disease (PD) was based on PSA progression with an increase of ≥25% and ≥2 ng/ml above the nadir since the start of therapy, which was 12 months (95% confidence interval (CI)=7.6-16.4 had to be confirmed 3 or more weeks later (11). Imaging studies months) (Figure 2). The median overall survival starting were not routinely used, but were based on clinical condition such from administration of AA was 25 months (95% CI=21.67- as symptomatic metastasis. According to the Response Criteria for 28.33 months) in the responsive group and 8 months (95%

5430 Hung et al : Outcome of mCRPC After PSA Progression on Abiraterone

Figure 1 . The distribution of patients according to clinical behavior. Fifty-nine out of 83 patients with PSA progression after abiraterone acetate therapy were eligible for this study.

CI=3.73-12.27 months) in the non-responsive group (log- rank p< 0.001) (Figure 3A). The median duration of survival starting from AA treatment failure was 13 months in the responsive group and 7 months in non-responsive group, without statistically significant difference (log-rank p= 0.126) (Figure 3B). Patients received subsequent therapy (re-challenge of chemotherapy or treatment of enzalutamide) after AA treatment failure appeared to have a superior survival duration in comparison with those treated with best supportive care, with a median overall survival of 18 months vs. 4 months, sequential therapy vs. not sequential therapy (log-rank p= 0.003) (Figure 4). Furthermore, in both univariate and multivariate Cox regression analyses, sequential therapy was positive correlated with superior Figure 2 . Survival curve of all patients after PSA progression after overall survival in patients with PSA progression after AA abiraterone acetate. The median survival was 12 months (interquartile (p= 0.005 and p= 0.01, respectively; Table III). range=3-18 months).

5431 ANTICANCER RESEARCH 38 : 5429-5436 (2018)

Table I. Basic characteristics of all patients before abiraterone acetate use.

Total (n=59) Value

Hormone-sensitive stage Median age at diagnosis (IQR), years 65 (60-74) Median primary PSA (IQR), ng/ml 113.24 (38.99-381.00) RRP, n (%) 13 (22.0%) RT, n (%) 14 (23.7%) Median Gleason score (IQR) 9 (7-9) Median duration of first-line line ADT (IQR), months 20.0 (10.0-35.5) CRPC stage (docetaxel and cabazitaxel) Median PSA (IQR), ng/ml 35.88 (11.25-120.75) Median no. of docetaxel cycles (n=59) (IQR) 6 (3-10) Median no. of cabazitaxel cycles (n=19) (IQR) 4 (3-5) Median duration of chemotherapy period (IQR), months 12.0 (6.0-22.0)

IQR: Interquartile range; PSA: prostatic-specific antigen; RRP: radical retropubic prostatectomy; RT: radiation therapy; ADT: androgen-deprivation therapy; CRPC: castration-resistance prostate cancer.

Table II. Characteristics of patients after prostatic-specific antigen (PSA) progression under abiraterone acetate (AA) therapy.

Total (n=59) Group p- Value

Characteristic Response (n=26) Non-response (n=33)

Median age at AA start (IQR), years 71 (64-78) 69 (62.5-78.0) 72 (66.5-79.5) 0.477 Median PSA pre-AA (IQR), ng/ml 75.26 (21.13-306.00) 56.25 (17.08-144.75) 90.44 (26.95-510.50) 0.228 Median best PSA on AA (IQR), ng/ml 51.12 (15.41-447) 18.55 (4.77-50.03) 287.00 (24.78-718.50) <0.001 Median duration of AA use (IQR), months 3.0 (2.0-6.0) 7.0 (4.0-13.5) 2.0 (2.0-3.0) <0.001 Median PSA (IQR) at PSA progression, ng/ml 96.56 (40.07-687.00) 60.33 (32.60-195.25) 211.00 (58.89-985.00) 0.023 Median ALP (IQR) at PSA progression, U/I 181.00 (121.00-405.00) 146.00 (124.50-283.00) 272.00 (100.75-484.50) 0.161 Median LDH (IQR) at PSA progression, U/I 256.00 (202.00-344.50) 249.00 (205.75-315.00) 290.50 (200.50-563.75) 0.403 Radiographic PD (bone and soft tissue), n (%) 42.00 (71.2%) 17.00 (65.4%) 25.00 (75.8%) 0.184 Response to chemotherapy rechallenge (n=16), n (%) 6.00 (37.5%) 1/8 (12.5%) 5/8 (62.5%) 0.039 Response to enzalutamide (n=13), n (%) 5 (38.5%) 4/10 (40.0%) 1/3 (33.3%) 0.835 Survival, n (%) 21 (35.6%) 12 (46.2%) 9 (27.3%) 0.133 Median follow-up time (IQR), months 11.0 (7-20) 19.5 (9.0-25.5) 7.0 (5.0-15.0) <0.001

IQR: Interquartile range; PD: progressive disease; ALP: alkaline phosphatase; LDH: lactic dehydrogenase. Radiographic PD defined as two new bone lesions or soft tissue metastasis ≥20% increase in size using RECIST criteria (12). Continuous variable analysis used Mann–Whitney U-test and Fisher’s exact tes t t- test, categorical variables analysis used Pearson Chi-square test, with significance acceptable at p< 0.05 (shown in bold).

Discussion Therefore, we expanded and continued to collect and record the post-chemotherapeutic clinical responses of patients with This study demonstrates real-world data of clinical course for mCRPC to AA treatment. In this study, all eligible patients patients with mCRPC and PSA progression after chemotherapy treated with AA had a median survival of 12 months after and AA treatment. Additionally, subsequent therapy provides a PSA progression developed. Among these patients, the AA- superior survival benefit after AA treatment failure. responsive group had better overall survival than the non- Our previous study evaluated the effect of AA on the responsive group (median of 25 vs. 8 months, p< 0.001). clinical outcome of patients with mCRPC who received AA In a final analysis of the COU-AA-301 study, Fizazi et al. treatment after docetaxel and provided evidence that clinical revealed that AA significantly prolonged overall survival in parameters, such as first-line ADT duration or pre-AA PSA patients with mCRPC whose disease progressed after level, may correspond to progression-free survival and serve docetaxel treatment and that the survival benefit in the AA- as simple predictors for the outcome of AA treatment (9). treated group compared to the placebo group was consistent

5432 Hung et al : Outcome of mCRPC After PSA Progression on Abiraterone

Figure 3. Kaplan–Meier survival curve for evaluation of overall survival according to response to abiraterone acetate (AA) of patients with metastatic castration-resistant prostate cancer. A: Overall survival according to AA use. The median survival of 25 months for the AA-responding group was significantly better than the 8 months for the AA non-responsive group (log-rank p<0.001). B: Overall survival after progression of disease on AA. The median survival of the responding group was 13 months, while the median survival of the non-responding group was 7 months (log-rank p=0.126).

across most protocol-specified subgroups. Their finding suggests that mCRPC remains androgen-driven and that the survival benefit of AA is independent of previous docetaxel therapy (7). AA is a selective inhibitor of an enzyme (CYP17A1) critical for androgen production. Enzalutamide, an inhibitor of AR, is another second-line therapy for mCRPC that acts on multiple steps of the AR signaling pathway. In this study, the effect of AA on overall survival for AA-responsive patients was significantly better than for non-responsive patients. Additionally, there was a 40% (4/10) response in AA-responsive patients who received enzalutamide treatment as subsequent therapy after PSA progression. Moreover, our previous study provided evidence that ADT-duration is related to AA efficacy (9). The observations from our series of clinical studies implied that in the AA-responsive Figure 4. Overall survival among patients who received sequential population, androgen-related signaling plays a critical role in therapy after PSA progression on abiraterone acetate and those who did driving the tumorigenesis and progression of prostate cancer, not. In patients who received sequential therapy, the median survival even in the late stage of advanced prostate cancer. In was 18 months, while it was only 4 months for those who did not (log- addition to our speculation, a pooled analysis of 10 case rank p=0.003). series for the treatment of enzalutamide after docetaxel and AA in mCRPC also suggests a greater benefit of enzalutamide in patients who responded to AA (13). However, Davies et al. studied a series of 34 patients that chemotherapy-naive patients with mCRPC whose disease receiving enzalutamide after docetaxel and AA and suggested progressed with AA treatment may still benefit from that the response to previous AA is not predictive of subsequent docetaxel therapy (15), which supports the need subsequent response to enzalutamide (14). for further assessment of treatment patterns following AA for A post-hoc analysis of the COU-AA-302 trial mCRPC, particularly among older patients. In our study, the (chemotherapy-naive men with mCRPC) investigated clinical median age of patients starting to receive AA was 71 years responses to docetaxel as the first subsequent therapy among (IQR=64-78 years) with a median Gleason score=9 (IQR 7- patients who developed PD following AA treatment. It found 9). Sequential therapy (re-challenge of chemotherapy or

5433 ANTICANCER RESEARCH 38 : 5429-5436 (2018)

Table III. Univariate and multivariate analysis for predictors of all-cause death after prostatic-specific antigen (PSA) progression under abiraterone acetate (AA) therapy by Cox regression, with significance acceptable at p<0.05.

Comparison HR (95%CI) p- Value HR (95%CI) p- Value

Age at AA start Per yearly increment 1.024 (0.989-1.061) 0.177 Initial PSA Per ng/mI increment 1.000 (0.999-1.000) 0.561 RRP Yes vs. no 0.674 (0.292-1.536) 0.348 Gleason score Per point increment 1.260 (0.846-1.875) 0.256 Hormone-sensitive period Per monthly increment 0.994 (0.978-1.011) 0.487 Chemotherapy period Per monthly increment 0.977 (0.947-1.007) 0.135 AA Period Per monthly increment 0.946 (0.886-1.011) 0.101 AA Response Response vs. non response 0.613 (0.316-1.187) 0.147 Age at PSA progression Per yearly increment 1.020 (0.986-1.056) 0.243 PSA at PSA progression Per ng/mI increment 1.000 (1.000-1.001) <0.001 1.000 (1.000-1.001) 0.092 Alk-P at PSA progression Per U/I increment 1.001 (1.000-1.002) 0.002 1.001 (0.999-1.002) 0.234 LDH at PSA progression Per U/I increment 1.001 (1.000-1.001) 0.013 1.000 (0.999-1.001) 0.862 Soft tissue PD Yes vs. no 2.717 (1.400-5.273) 0.003 2.109 (0.833-5.335) 0.115 Bone metastasis PD Yes vs. no 3.314 (1.447-7.588) 0.005 7.159 (1.830-28.011) 0.005 Subsequent therapy Yes vs. no 0.364 (0.179-0.742) 0.005 0.270 (0.099-0.736) 0.010

HR, Hazard ratio; CI, confidence interval; RRP: radical retropubic prostatectomy; PD: progressive disease; ALP: alkaline phosphatase; LDH: lactic dehydrogenase. Significance acceptable at p< 0.05 (shown in bold).

administration of enzalutamide) showed a positive correlation challenge in patients, especially those who are non- to a superior overall survival in post-chemotherapeutic responsive to AA, may require further exploration. mCRPC patients with PD after AA (multivariate analysis, Zhang et al. reported clinical cross-resistance in men with HR=0.270, 95% CI=0.099-0.736, p= 0.010). In addition, a mCRPC who had disease progression during AA treatment. better response rate for chemotherapy re-challenge in the AA The cross-resistance appeared more frequently with non-responsive group was obtained in our study (responsive enzalutamide and less in docetaxel-treated groups (16). This vs. non-responsive groups, 12.5% vs. 62.5%, p= 0.039). The finding suggests that patients whose disease is initially analyzed results from our patients might echo those of resistant to AA and who have a PSA response during previous studies, in which docetaxel had an impactful subsequent docetaxel treatment may have a different (non– antitumor activity as the first subsequent therapy for patients AR-related) mechanism of resistance to AA or enzalutamide. with mCRPC who experienced PSA progression on AA (15), Thus, this coincides with the result of our study that the with a modest activity for enzalutamide and docetaxel in response rate to docetaxel was significantly higher in the AA progressive mCRPC after AA (16). non-responsive group. The usage of AA for patients with mCRPC has changed The treatment strategy for mCRPC has been discussed in the therapeutic situation for prostate cancer. Although AA several studies (20-22), but the optimal sequencing of these increases the survival opportunities of patients with mCRPC, innovative therapies remains unclear. The re-challenge of this agent is unfortunately not curative. Ultimately, drug docetaxel at occurrence of PD after AA showed that in order resistance often develops. The phenomenon of cross- to maintain antitumor activity in mCRPC in selective resistance among AA, enzalutamide and taxanes has been patients, a valid treatment option for patients with favorable investigated in recent years (17, 18). Androgen receptor response to first-line docetaxel may be required (23). splice variants, namely ARv567 and ARv7, may contribute Although the nature of our study and the small number of to resistance to these drugs. Van Soest et al. found an patients did not allow for definitive conclusions, our study impaired efficacy of docetaxel, cabazitaxel and enzalutamide provides evidence for the clinical benefit of subsequent in an abiraterone-resistant cell line, suggesting cross- chemotherapy re-challenge in docetaxel/cabazitaxel pre-treated resistance between taxanes and hormonal agents such as patients mCRPC with disease progression after AA treatment. abiraterone and enzalutamide (19). The preclinical evidence In summary, for docetaxel/cabazitaxel-pre-treated patients for cross-resistance between taxanes and AR-targeting agents with mCRPC who suffer from PSA progression after AA, may not be consistent with our finding that there was still a subsequent therapy with chemotherapy re-challenge or response rate of 37.5% to chemotherapy re-challenge in the enzalutamide application may contribute to a better survival AA non-responsive group. The efficacy of chemotherapy re- benefit. Our findings may also provide the basis for

5434 Hung et al : Outcome of mCRPC After PSA Progression on Abiraterone management of sequential therapy in the terminal stage of Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI and C.-A.-. prostate cancer. Investigators: Abiraterone and increased survival in metastatic In addition to a retrospective setting, other limitations of prostate cancer. N Engl J Med 364(21) : 1995-2005, 2011. 7 Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, this study were a small sample size and the treatment Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, protocol, while the follow-up schedule, PSA check-up Harland S, Goodman OB Jr., Sternberg CN, Li JH, Kheoh T, schedule and other variables were not well controlled. The Haqq CM, de Bono JS and C.-A.-. Investigators: Abiraterone performance of subsequent treatment may also have been acetate for treatment of metastatic castration-resistant prostate biased due to preference or burden considerations. cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Conclusion Lancet Oncol 13(10) : 983-992, 2012. 8 Kwak C, Wu TT, Lee HM, Wu HC, Hong SJ, Ou YC, Byun SS, Rhim HY, Kheoh T, Wan Y, Yeh H, Yu MK and Kim CS: In our small retrospective patient experience, effectively Abiraterone acetate and prednisolone for metastatic castration- sequential treatments for patients with mCRPC provided an resistant prostate cancer failing androgen deprivation and overall survival benefit. Previous treatment response can act docetaxel-based chemotherapy: a phase II bridging study in Korean as a clinical predictor for subsequent treatment. and Taiwanese patients. Int J Urol 21(12) : 1239-1244, 2014. 9 Li JR, Wang SS, Yang CK, Chen CS, Ho HC, Chiu KY, Hung Human Ethical Statement CF, Cheng CL, Yang CR, Chen CC, Wang SC, Lin CY and Ou YC: First Line androgen deprivation therapy duration is Certification of approval with IRB: CE13240A-2. associated with the efficacy of abiraterone acetate treated metastatic castration-resistant prostate cancer after docetaxel. Conflicts of Interest Front Pharmacol 13(8) : 55, 2017. 10 Omlin A, Pezaro C and Gillessen Sommer S: Sequential use of novel therapeutics in advanced prostate cancer following None of the contributing Authors have any conflict of interest, docetaxel chemotherapy. Ther Adv Urol 6(1) : 3-14, 2014. including specific financial interests or relationships and affiliations, 11 Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci relevant to the subject matter or materials discussed in the MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak manuscript. 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17 Petrioli R, Francini E, Laera L, Fiaschi AI, Ponchietti R and 21 van Dodewaard-de Jong JM, Verheul HM, Bloemendal HJ, de Roviello G: Role of chemotherapy in the treatment of metastatic Klerk JM, Carducci MA and van den Eertwegh AJ: New castration-resistant prostate cancer patients who have progressed treatment options for patients with metastatic prostate cancer: after abiraterone acetate. Cancer Chemother Pharmacol 76(3) : What is the optimal sequence? Clin Genitourin Cancer 13(4) : 439-445, 2015. 271-279, 2015. 18 Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser 22 van Soest RJ, de Morree ES, Kweldam CF, de Ridder CMA, JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Wiemer EAC, Mathijssen RHJ, de Wit R and van Weerden WM: Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller Targeting the androgen receptor confers in vivo cross-resistance CJ, Denmeade SR, Carducci MA, Eisenberger MA and Luo J: between enzalutamide and docetaxel, but not cabazitaxel, in AR-V7 and resistance to enzalutamide and abiraterone in castration-resistant prostate cancer. Eur Urol 67(6) : 981-985, prostate cancer. N Engl J Med 371(11) : 1028-1038, 2014. 2015. 19 van Soest RJ, van Royen ME, de Morree ES, Moll JM, Teubel 23 Petrioli R, Francini E and Roviello G: Is there still a place for W, Wiemer EA, Mathijssen RH, de Wit R and van Weerden docetaxel rechallenge in prostate cancer? World J Clin Oncol WM: Cross-resistance between taxanes and new hormonal 6(5) : 99-103, 2015. agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer 49(18) : 3821-3830, 2013. 20 Sonpavde G, Bhor M, Hennessy D, Bhowmik D, Shen L, Nicacio L, Rembert D, Yap M and Schnadig I: Sequencing of cabazitaxel and abiraterone acetate after docetaxel in metastatic castration-resistant prostate cancer: treatment patterns and Re ceived June 23, 2018 clinical outcomes in multicenter community-based us oncology Revised July 11, 2018 practices. Clin Genitourin Cancer 13(4) : 309-318, 2015. Accepted July 16, 2018

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